Alcohol consumption can cause alcoholic liver disease (ALD), which is a major cause of morbidity and mortality in the United States. Also, it remains unclear why only some heavy drinkers develop clinically relevant ALD. Unfortunately, there is no FDA-approved therapy for any stage of ALD, and the pathogenesis of ALD is not fully understood. Therefore, it is critical to investigate the underlying mechanisms and pathogenic mediators in order to identify novel targets and therapeutic strategies in ALD. Chronic alcohol consumption causes a prooxidant environment in the liver and increases hepatic lipid peroxidation (LPO), which produces lipid-derived aldehydes such as acrolein, one of the most reactive and toxic aldehydes. Acrolein is primarily metabolized/cleared by conjugation to glutathione (GSH) catalyzed by glutathione-S-transferase-Pi (GSTP); unless removed, acrolein can adversely impact key cellular functions. Acrolein can form covalent irreversible adducts with cellular molecules with detrimental consequences; such acrolein adducts are associated with several diseases. Our data show that acrolein exposure in hepatocytes causes endoplasmic reticulum (ER) stress, GSH depletion and apoptosis, all of which are recognized etiologic factors in ALD. Further, our preliminary data show alcohol consumption downregulates GSTP and causes significant hepatic acrolein generation/accumulation, which correlates with steatosis, inflammation and liver injury in mice. This project will test our hypothesis that acrolein critically mediates alcohol-induced ER stress and liver injury, thereby contributing to ALD pathogenesis. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury, and may help identify new therapeutic targets and potential interventions for ALD.